EP1295872A1 - Composition medicamenteuse antagoniste pour les recepteurs de pgd2/txa2 - Google Patents
Composition medicamenteuse antagoniste pour les recepteurs de pgd2/txa2 Download PDFInfo
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- EP1295872A1 EP1295872A1 EP01934363A EP01934363A EP1295872A1 EP 1295872 A1 EP1295872 A1 EP 1295872A1 EP 01934363 A EP01934363 A EP 01934363A EP 01934363 A EP01934363 A EP 01934363A EP 1295872 A1 EP1295872 A1 EP 1295872A1
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- 0 ****[C@@]([C@]1C[C@@]2CC1)[C@@]2C=CCCCC(O)=O Chemical compound ****[C@@]([C@]1C[C@@]2CC1)[C@@]2C=CCCCC(O)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a dual antagonist against thromboxane A 2 and prostagrandin D 2 receptors and in detail, a compound having a [2. 2. 1] or [3. 1. 1.] bicyclo skeleton.
- PGD 2 receptor antagonists have a quite different character from that of TXA 2 receptor antagonists in the site and mechanism of action and indications thereof.
- a compound having a dual antagonistic activity against both a TXA 2 receptor and a PGD 2 receptor can be useful as therapeutic agents for various diseases caused by TXA 2 or PGD 2 .
- TXA 2 causes potent tracheal contraction and respiratory anaphylaxis and PGD 2 effects infiltration of eosionophils.
- PGD 2 effects infiltration of eosionophils.
- TXA 2 and PGD 2 are thought to be one of causative substances of the pathopoiesis and advance of asthma, thus the dual antagonistic compounds are expected to be more potent agents for treating asthma than ever known antagonists.
- the dual antagonistic compounds are expected to be more potent agents for treating nasal blockage than known antagonists.
- the present inventors have studied intensively to develop a pharmaceutical composition having a dual antagonistic activity against TXA 2 /PGD 2 receptors and found out new compounds and pharmaceutical compositions comprising them.
- the present invention provides:
- a compound of the present invention has a special feature at A and R and has an improved metabolic property. Further, a compound of the present invention is a dual antagonistic activity against PGD 2 /TXA 2 receptors having the above mentioned features (A) to (D).
- a preferred embodiment is a compound of the formula (I) wherein
- Alkylene used herein means a straight chain and branched chain C1 to C9 and refers to methylene, methylmethylene, dimethylmethylene, ethylmethylmethylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, and the like.
- heteroaryl includes a group which has a bond at any substitutable position and which can be converted from a 5- to 7-membered aromatic heterocycle containing one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic heterocycle as fused with one or more carbocycle or other aromatic heterocycle. Any one of aromatic heterocycle and aromatic carbocycle may have a bond.
- Heteroaryl may have a bond at a nitrogen atom as well as a carbon atom of aromatic heterocycle or aromatic carbocycle.
- heteroaryl examples include pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), carbazolyl (e.g.
- aromatic carbocycle or other aromatic heterocycle which may fuse the above “heteroaryl” includes 5- to 7-membered aromatic cycle which may contains one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic ring as fused with one or more other aromatic rings.
- aryl includes mono aromatic carbocyclyl (e.g., phenyl) or fused aromatic carbocyclyl (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, 9-anthryl, 1-phenanthryl, 10-phenanthryl).
- non-aromatic heterocyclyl includes a group which has a bond at any substitutable position and which can be converted from 3- to 7-membered non-aromatic heterocyclyl which contains one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or non-aromatic heterocyclyl which is fused with a carbon ring (e.g. aromatic carbocycle) or other heterocyclyl (e.g. aromatic heterocycle).
- the substitutable bond may exist not only on the carbon atom but also on the nitrogen atom in the non-aromatic heterocyclyl.
- Examples are aziridinyl, piperidino, piperidinyl, morphorino, morphorinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, piperadino, piperadinyl, isooxazolinyl, thiolanyl, tetrahydrofuranyl, dioxanyl, oxathianyl, tetrahydropyranyl, and the like.
- Preferable is 5- or 6-membered non-aromatic heterocyclyl containing a nitrogen atom.
- the following groups are exexplified as a group which has a bond at any substitutable position and which can be converted from non-aromatic heterocyclyl fused with one or more carbon ring (e.g. aromatic carbocycle) or other heterocyclyl (e.g. aromatic heterocycle): Furthermore, the substitutable bond may exist at any position of the carbon atom or the nitrogen atom.
- Aryl or “heteroaryl” may be fused 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle.
- cycloalkane include cyclobutane, cyclopentane, cyclohexane, and cycloheptane.
- non-aromatic heterocycle include pyrrolidine, piperazine, oxorane, 1,3-dioxorane, 1,4-dioxane, thiorane, or the like.
- the above “cycloalkane” and “non-aromatic heterocycle” may be fused with other aromatic carbocycle or aromatic heterocycle. Examples of aryl or heteroaryl fused with 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle are illustrated below.
- Alkyl includes a straight or branched C1 to C8 alkyl group or a C3 to C8 cycloalkyl group. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- Haloalkyl includes a straight or branched C1 to C8 alkyl or C3 to C8 cycloalkyl group substituted with one or more halogen, for example, chloromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dichloroethyl or the like.
- halogen for example, chloromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dichloroethyl or the like.
- Alkenyl includes a straight or branched C2 to C8 alkenyl or C3 to C8 cycloalkenyl group having one or more double bond(s), for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl or the like.
- Alkynyl includes a straight or branched C2 to C8 alkynyl having one or more triple bond(s), for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl or the like.
- Halogen includes fluoro, chloro, bromo, and iodo.
- alkyl used in the term “arylalkyl” or “heteroarylalkyl” have the same meaning of the above “alkyl”
- aryl used in the term “arylalkyl”
- heteroaryl used in the term “heteroarylalkyl” have the same meaning of the above “heteroaryl”.
- Hydroxy alkyl includes the above “alkyl” substituted with one or two hydroxy, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1,2-dihydroxy-n-propyl or the like.
- substituent of "optionally substituted amino” or “optionally substituted amino alkyl” include the above “alkyl”, the above “arylalkyl”, the above “aryl”, the above “heteroaryl”, the above “heteroarylalkyl” hydroxy.
- Alkylsulfonyl, or the like They may be mono- or di-substituted with these substituents.
- alkyl may form a ring together with a nitrogen atom of an amino group.
- Example of "optionally substituted amino” includes amino, N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylamino, pyrrolidino, piperidino, N-methyl-N-phenylamino, isopropylamino, diisopropylamino, hydroxyamino, alkylsulfonylamino (e.g., methanesulfonylamino, ethanesulfonylamino, etc.), arylsulfonyl (e.g., benzenesulfonylamino, toluenesulfonylamino, etc.), N-alkyl-N-alkylsulfonylamino (e.g., N-methyl-N-methanesulfonylamino, etc.), halogenated alkylsulfonylamino (e.g., triflu
- optionally substituted aminoalkyl examples include N,N-dimethylaminomethyl, N-ethyl-N-methylaminomethyl, N,N-diethylaminomethyl, pyrrolidinomethyl, piperidinomethyl, N-methyl-N-phenylaminomethyl, isopropylaminomethyl, diisopropylaminomethyl or the like.
- a pharmaceutical composition having a dual antagonistic activity against PGD 2 /TXA 2 receptors means a pharmaceutical composition comprising at least one compound of the formula (I) having an antagonistic activity against both a PGD2 receptor and a TXA 2 receptor.
- the other active agents e.g. antiinflammatory agents, antiallergy agents and the like
- pharmaceutically acceptable admixtures e.g., binding agent, filler and the like
- the compound of the present invention has an antagonistic activity against PGD 2 receptor and TXA 2 receptor and can exhibit antagonistic activities against PGD 2 receptor and TXA 2 receptor in vivo.
- the compound administered can not always exhibit both of the antagonistic activity in vivo, owing to the preferential binding to the receptor of stronger affinity. Therefore, as a compound of the present invention, preferable is that the compound has antagonistic activities against PGD 2 and TXA 2 receptors and is 100 times, preferably 50 times and more preferably ca. 10 times in a ratio between affinities against PGD 2 and TXA 2 receptors.
- the ratio between affinities against PGD 2 and TXA 2 receptors can be calculated by the use of IC 50 values and the like.
- a compound of the present invention preferable is less than 0.1 ⁇ M in the binding activity against TXA 2 receptor using human platelet membrane (IC 50 value) and 0.1 ⁇ M in the antagonistic activity against PGD 2 receptor using human platelet (IC 50 value).
- the compound is preferable, in which both of the binding activity against TXA 2 receptor using human platelet membrane (IC 50 value) and the antagonistic activity against PGD 2 receptor using human platelet (IC 50 value) are less than 0.1 ⁇ M.
- the compound is preferable, in which their ratio is 100 times, preferably 50 times and more preferably ca. 10 times.
- the present invention includes a method for treating asthma, nasal blockage, allergic conjunctivitis or allergic rhinitis which comprises administering a compound of the formula (I) and use of a compound of the formula (I) for manufacturing a medicine for asthma, nasal blockage allergic conjunctivitis or allergic rhinitis.
- ⁇ chain means a group represented by the formula: "A-R 1 , and " ⁇ chain” means a group represented by the formula:
- E and Z mean E-form and Z-form in double bond of each formula, respectively.
- Each sign in 4A to 9B means an A part of the formula and means the same group in Table 1 to Table 15 in this description.
- R are COOH, COOMe, CONH 2 , CONHSO 2 Me, CH 2 OH, CH 2 OMe, CONHMe, CON(Me)SO 2 Me, 5-tetrazolyl, CONHSO 2 Ph, CONHSO 2 CF 3 and the like.
- combination of A and R includes all of the combination and preferable is a combination described in Table 1 to Table 15.
- each sign of 1 to 513 below means a group shown by the formula: -X 1 -X 2 -X 3 and the compound number both in Table 1 to Table 15 and in Examples of reference in the present invention means the same group.
- a compound of the present invention can be any of the following stereo isomers of [2.2.1] and [3.1.1] bicyclic skeleton.
- the present invention includes all stereo isomers of them and the optional mixtures thereof. Namely, the bond binding to the bicyclic ring is in R configuration or S configuration, and all of the stereo isomers (diastereomer, epimer, enantiomer and the like), racemates, and optional mixture thereof are included in the present invention.
- the ⁇ chain of the compound of the present invention can be in Z configuration or E configuration, thus a compound having any of the configurations and the mixture thereof are included in the present invention.
- a prodrug of a compound of the formula (I) is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition.
- Method for the selection and process of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985.
- an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide derivative prepared by reacting a basal acid compound with a suitable amine is exemplified as a prodrug.
- a particularly preferred ester derivative as an prodrug is an optionally substituted alkyl ester derivative (e.g., methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester), an arylalkyl ester derivative (e.g., benzyl ester, phenethyl ester, benzhydryl ester), or the like.
- alkyl ester derivative e.g., methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester
- an arylalkyl ester derivative e.g., benzyl ester, phenethyl este
- a particularly preferred amide derivative as a prodrug is alkyl amide derivative (e.g., N-methyl amide, N-ethyl amide, N-(n-propyl)amide, N-isopropyl amide, N-(n-butyl)amide, N-isobutyl amide, N-(tert-butyl)amide), aryl alkyl amide (e.g., N-benzyl amide, N-phenethyl amide, benzhydryl amide), or the like.
- alkyl amide derivative e.g., N-methyl amide, N-ethyl amide, N-(n-propyl)amide, N-isopropyl amide, N-(n-butyl)amide, N-isobutyl amide, N-(tert-butyl)amide
- aryl alkyl amide e.g., N-benzyl amide, N-phenethyl amide,
- an acyloxy derivative prepared by reacting with a suitable acyl halide e.g., acid chloride, halogenated acid
- a suitable acid anhydride e.g., mixed acid anhydride
- a particularly preferred acyloxy derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyloxy (e.g., -OCOC 2 H 5 , -OCO(tert-Bu), -OCOC 15 H 31 , -OCOCH 2 CH 2 COONa, -OCOCH(NH 2 )CH 3 , -OCOCH 2 N(CH 3 ) 2 -), optionally substituted arylcarbonyloxy (e.g., -OCO(m-COONa-Ph) or the like.
- optionally substituted alkylcarbonyloxy e.g., -OCOC 2 H 5 , -OCO(tert-Bu)
- optionally substituted arylcarbonyloxy e.g., -OCO(m-COONa-Ph
- an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug.
- a particularly preferred amide derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyl (e.g., -NHCO(CH 2 ) 20 CH 3 , -NHCOCH(NH 2 )CH 3 ) or the like.
- Examples of a salt of the compound of the formula (I) or its prodrug include alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline-earth metal salts such as calcium salts, salts with organic bases such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylene methylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthorathene, 2-amin
- a solvate means a solvate with an organic solvent, a hydrate and the like of the compound of the formula (I), its prodrug or its pharmaceutically acceptable salt, for example, monohydrate, dihydrate or the like.
- A is alkylene optionally intervened with a heteroatom, optionally having an oxo group, optionally substituted with halogen and/or optionally having an unsaturated bond
- R 1 is hydroxy, alkyloxy, or optionally substituted amino
- the compound of the formula (I) can be prepared by reacting a carboxylic acid of the formula (M-2) or its reactive derivative with an amino compound of the formula (M-1).
- the reactive derivatives of carboxylic acid of the formula (M-2) mean the corresponding acid halides (e.g., chloride, bromide, iodide), anhydrides (e.g., mixed anhydride with formic acid or acetic acid), active esters (e.g., N-hydroxysuccinimide ester), and the like, and include acylating agents used for the usual acylation of amino group.
- acid halides e.g., chloride, bromide, iodide
- anhydrides e.g., mixed anhydride with formic acid or acetic acid
- active esters e.g., N-hydroxysuccinimide ester
- an acid halide is obtained by reacting the compound (M-2) with a thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), and the like, in accordance with known methods as described in the literatures.
- a thionyl halide e.g., thionyl chloride
- phosphorous halide e.g., phosphorous trichloride, phosphorous pentachloride
- oxalyl halide e.g., oxalyl chloride
- the reaction can be conducted under a condition generally used for the acylation of amino group.
- a solvent such as an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane), benzene solvent (e.g., benzene, toluene, xylene), halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform) as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, or the like, if necessary, in the presence of a base (e.g., organic base such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine; inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, or the like) under cooling, at room temperature, or
- a base e.g., organic base such as trieth
- R of a compound represented by the formula (M-1) is a carboxyl group
- a free form may be used without converting the carboxy group (M-2) into the reactive derivatives and the reaction may be conducted in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-methylaminopropyl)carbodiimide, N,N'-carbonyldiimidazole, or the like) usually used in the condensation reaction of amine and carboxylic acid.
- DCC dicyclohexylcarbodiimide
- 1-ethyl-3-(3-methylaminopropyl)carbodiimide N,N'-carbonyldiimidazole, or the like
- reaction conditions are determined according to the property of each reactive derivative or free acid, in accordance with a known method.
- the reaction product can be purified in accordance with a conventional purification, such as the extraction with a solvent, chromatography, recrystallization, and the like.
- a derivative of the ester or the amide can be prepared by esterification or amidation, in accordance with the well known method.
- the ester derivative can be converted by reduction to an alcoholic derivative, which can be derived to an ether derivative by O-alkylation.
- a compound in which R is 5-tetrazolyl can be prepared by converting an amide derivative having R; CONH2 to R: CN by dehydration in accordance with the well known method, followed by a reaction with sodium azide (J. Am. Chem. Soc. 1958, 80, 3908) or trimethylsilylazide (J. Org. Chem. 1993, 58, 4139).
- the other starting compounds can be prepared from the aldehyde derivative (Q is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like) represented by a general formula (M-1a) or (M-1b) by one or more reaction(s) of an ylide compound under a Wittig reaction condition (Org. Reaction, 1965, 14, 270) in combination with other reactions.
- Q is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like
- M-1a a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like
- R is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like
- R is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like
- R is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the
- the compound M-5D is hydrogenated in the presence of palladium, platinum and the like to give a starting material (M-5A), wherein A is -CH 2 -CH 2 -CH 2 -CH 2 -.
- Amidation with a starting carboxylic acid (M-2) can be accomplished after a deprotection of an amino protecting group Q in a way of conversion to ⁇ -chain, if necessary.
- the carboxylic acid of the formula (M-2) can be prepared by reacting a carboxylic acid having X 1 or its reactive derivative with a compound having X 3 .
- a person ordinary skilled in the art can carry out such a reaction by selecting the kinds of reactions and their conditions depending on the kind of X 2 .
- a group of the formula: -NHCO-X 1 -X 2 -X 3 of the compound (I) can be introduced by reacting a carboxylic acid of the formula: X 3 -X 2 -X 1 -COOH (M-2) or its reactive derivative with amine (M-1), or by reacting a carboxylic acid having X 1 or its reactive derivatives with amine (M-1) and reacting the obtained compound with a compound having X 3 .
- the compound having an aromatic heterocycle substituted with a nitro group can be prepared through the nitration of the compound with a nitrating acid.
- the compound having an aromatic heterocycle substituted with an amino group can be prepared through the reduction of the above-obtained compound with tin in the presence of hydrochloride.
- the compound having an aromatic heterocycle substituted with hydroxy group can be prepared through the diazonization of the above-obtained compound and the hydrolysis with alkali.
- the compound having an aromatic heterocycle substituted with an alkoxy group can be prepared through the reaction of the diazonium derivative with alcohol.
- the compound having an aromatic heterocycle substituted with halogen can be prepared through Sandmeyer reaction, the reaction of the diazonium derivative with a copper salt (e.g., CuCl 2 , CuBr 2 ).
- the compound having an aromatic heterocycle substituted with halogen can be also prepared through the direct reaction of the compound having an aromatic heterocycle with chlorine and the like. Using the above-mentioned methods appropriately, halogen can be introduced into a desired position(s).
- the group of alkyl, alkenyl or acyl group can be directly introduced into an aromatic heterocycle through Friedel Crafts reaction with alkylating agent, an alkenylating agent, or an acylating agent, respectively, in the presence of anhydrous aluminum chloride and the like.
- the objective compound (I) of the present invention can be converted into a corresponding ester derivative, if desired.
- the ester derivative can be prepared by esterification of a carboxylic acid in accordance with a known method.
- a pharmaceutical composition containing the compound (I) of the present invention can be in the form for oral and parenteral administration. Specifically, it can be formulated into formulations for oral administration such as tablets, capsules, granules, powders, syrup, and the like; or those for parenteral administration such as injectable solution or suspension for intravenous, intramuscular, or subcutaneous injection, inhalant, eye drops, nasal drops, suppositories, or percutaneous formulations such as ointment.
- auxiliary components include pharmaceutically acceptable excipients such as binders (e.g., cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., starch sodium glycolate) or lubricants (e.g., magnesium stearate). Tablets may be coated appropriately.
- binders e.g., cornstarch
- fillers e.g., lactose, microcrystalline cellulose
- disintegrants e.g., starch sodium glycolate
- lubricants e.g., magnesium stearate
- liquid formulations such as syrups, solutions, or suspensions
- suspending agents e.g., methyl cellulose
- emulsifiers e.g., lecithin
- preservatives e.g., preservatives
- injectable formulations it may be in the form of solution, suspension, or oily or aqueous emulsion, which may contain suspension-stabilizing agents or dispersing agent, and the like.
- inhalant it is formulated into a liquid formulation applicable to an inhaler.
- eye drops it is formulated into a solution or a suspension.
- a nasal drug for treating nasal blockage it can be used as a solution or suspension prepared by a conventional formulating method, or administered as a powder formulated using a powdering agent (e.g., hydroxypropyl cellulose, carbopole) into the nasal cavity.
- a powdering agent e.g., hydroxypropyl cellulose, carbopole
- aerosol filled into a special container together with a solvent of low boiling point e.g., hydroxypropyl cellulose, carbopole
- an eyewash drug for treating allergic conjunctivitis it can be used as a solution or suspension of the compound or can be used by solving or suspending the compound before use.
- a stabilizing agent, solubilizing agent, suspending agent, emulsifier, buffer, preservatives and the like can be included.
- aseptic treatment is preferable.
- the daily dosage can generally be between 0.01 - 100 mg, preferably 0.01 - 10 mg, more preferably 0.01 - 1 mg, per kg body weight.
- the daily dosage can generally be between 0.001 - 100 mg, preferably 0.001 - 1 mg, more preferably 0.001 - 0. 1 mg, per kg body weight.
- the daily dosage can be administered in 1 - 4 divisions.
- Methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (2.94 ml, 13.92 mmol) and 18-crown-6 (5.52 g, 20.88 mmol) in THF (100 ml) were cooled at -60°C.
- a solution of potassium bis(trimethylsilyl)amide (0.5 M toluene solution, 27.8 ml, 13.9 mmol) was added.
- the mixture was stirred for 15h.
- a solution of compound (4) (2.0 g, 6.96 mmol) in THF (20 ml) was added dropwise during 15 min. The mixture was stirred at the same temperature for 2h.
- Diisopropylaluminum hydride (1M toluene solution, 13.1 ml, 13.1 mmol) was added dropwise to a solution of compound (5) (1.80 g, 5.24 mmol) in dichloromethane (20 ml)-hexane (20 ml) at -78°C. The mixture was stirred at the temperature for 1h. Methanol (1 ml) was added. The mixture was warmed to the room temperature. 2N Hydrochloric acid was added. The mixture was extracted with ethyl acetate.
- Potassium t-butoxide (6.73 g, 60.0 mmol) was added to a suspension of 2-(1,3-dioxolan-2-yl)ethyltriphenylphosphonium bromide (13.28 g, 30.0 mmol) in THF (60 ml) at -30°C. The mixture was stirred at -30°C to 0°C for 1h. A solution of compound (8) (5.62 g, 20.0 mmol) in THF (40 ml) was added dropwise at -25°C during 15min. The mixture was warmed to 0°C, stirred for 1.5h, diluted with water and extracted with ethyl acetate.
- Trifluoroacetic acid (3.82 ml, 49.5 mmol) was added to a solution of compound (10) (2.35 g, 6.19 mmol) in dicholoromethane (38 ml) and the mixture was stirred at room temperature for 3h and concentrated under a reduced pressure. The residue was dissolved in toluene (50 ml) and water (10 ml). 2N Sodium hydroxide was added to be alkaline in the aq. layer. The toluene phase was separated, washed with water and brine, dried and concentrated to give a compound (11) (1.70 g; yield 98%).
- Oxalyl chloride (0.236 ml, 2.71 mmol) and N,N-dimethylformamide (a drop) were added to a solution compound (12) (840 mg, 2.26 mmol) in dichloromethane (20 ml) with cooling in ice. The mixture was stirred for 30min and concentrated under a reduced pressure. The residue was dissolved in dichloromethane (20 ml). Methanesulfonamide (258 mg, 2.71 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.744 ml, 4.97 mmol) were added.
- 5-Bromothiophene-2-sulfonyl chloride was reacted directly with a pyrrole derivative or the acid chloride was converted to the sulfonamide followed by condensation with 2,5-dimethoxytetrahydro-derivative to give a sulfonylpyrrole derivative. Then, the product was converted to the organolithium or the organomagnesium compound by a halogen-metal exchange reaction, followed by reacting with carbon dioxide to give a desired compound.
- a compound with a beginning number "I-” means a compound of the formula:
- a compound with a beginning number "II-” means a compound of the formula:
- a compound with a beginning number "III-” means a compound of the formula:
- a compound with a beginning number "IV-” means a compound of the formula:
- a compound with a beginning number "V-” means a compound of the formula:
- a compound with a beginning number "VI-” means a compound of the formula:
- a number following the number (I, II, III, IV, V, and VI) represents a structure of the group of the formula: -X 1 -X 2 -X 3 and each number is the same meaning as that used in the list of the structure of the formula: -X 1 -X 2 -X 3 .
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000166305 | 2000-06-02 | ||
JP2000166305 | 2000-06-02 | ||
PCT/JP2001/004430 WO2001094309A1 (fr) | 2000-06-02 | 2001-05-28 | Composition medicamenteuse antagoniste pour les recepteurs de pgd2/txa2 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1295872A1 true EP1295872A1 (fr) | 2003-03-26 |
EP1295872A4 EP1295872A4 (fr) | 2007-05-16 |
Family
ID=18669644
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01934363A Withdrawn EP1295872A4 (fr) | 2000-06-02 | 2001-05-28 | Composition medicamenteuse antagoniste pour les recepteurs de pgd2/txa2 |
Country Status (5)
Country | Link |
---|---|
US (1) | US7084136B2 (fr) |
EP (1) | EP1295872A4 (fr) |
JP (1) | JPWO2001094309A1 (fr) |
AU (1) | AU2001260627A1 (fr) |
WO (1) | WO2001094309A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1338594A1 (fr) * | 2000-11-01 | 2003-08-27 | Shionogi & Co., Ltd. | Compositions pharmaceutiques antagonistes du recepteur de pgd2 |
US7674912B2 (en) | 2005-04-25 | 2010-03-09 | H. Lundbeck A/S | Pro-drugs of N-thiazol-2-yl-benzamide derivatives |
US7910613B2 (en) | 2004-09-22 | 2011-03-22 | H. Lundbeck A/S | 2-acylaminothiazole derivatives |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ516633A (en) * | 1999-06-21 | 2004-09-24 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof |
US7019012B2 (en) * | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
AR039280A1 (es) * | 2002-04-11 | 2005-02-16 | Smithkline Beecham Corp | Compuesto de aminotiofeno y su uso para preparar una composicion farmaceutica |
DE10221018A1 (de) * | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie |
US7321001B2 (en) | 2002-12-20 | 2008-01-22 | Amgen Inc. | Asthma and allergic inflammation modulators |
US7223749B2 (en) * | 2003-02-20 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
PL1725553T3 (pl) | 2004-03-11 | 2008-10-31 | Idorsia Pharmaceuticals Ltd | Pochodne tetrahydropirydoindolu |
CA2629244C (fr) | 2005-11-11 | 2014-08-05 | Boehringer Ingelheim International Gmbh | Derives de quinazoline pour le traitement des affections cancereuses |
ES2385613T3 (es) * | 2006-09-18 | 2012-07-27 | Boehringer Ingelheim International Gmbh | Método para tratar cánceres que portan mutaciones de EGFR |
CA2707789A1 (fr) | 2007-12-19 | 2009-07-09 | Amgen Inc. | Derives de l'acide phenylacetique utiles comme modulateurs de l'inflammation |
WO2011003853A2 (fr) | 2009-07-06 | 2011-01-13 | Boehringer Ingelheim International Gmbh | Procédé de séchage du bibw2992, de ses sels et des préparations pharmaceutiques solides contenant ce principe actif |
US9242965B2 (en) | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030683A1 (fr) * | 1998-11-19 | 2000-06-02 | Shionogi & C0., Ltd. | Composes prophylactiques et/ou therapeutiques destines a des maladies du systeme nerveux central et possedant des composes antagonistes du recepteur de txa2 et/ou inhibiteurs de la txa2 synthase |
WO2000053573A1 (fr) * | 1999-03-10 | 2000-09-14 | Shionogi & Co., Ltd. | Compositions medicinales renfermant des composes a squelette [2.2.1] et [3.1.1] bicycliques possedant des proprietes antagonistes vis-a-vis des recepteurs de pgd2/txa¿2? |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4037941A1 (de) | 1990-11-23 | 1992-05-27 | Schering Ag | Cyclopentanetherderivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
DE4225488A1 (de) | 1992-07-30 | 1994-02-03 | Schering Ag | Neue Bicyclo[3.3.0]octan-Derivate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung |
AU714312B2 (en) * | 1995-06-21 | 1999-12-23 | Shionogi & Co., Ltd. | Bicyclic amino derivatives and PGD2 antagonist containing them |
EP1016660B1 (fr) | 1997-09-19 | 2003-10-29 | Shionogi & Co., Ltd. | Composes ayant un squelette 2.2.1]bicyclo |
-
2001
- 2001-05-28 EP EP01934363A patent/EP1295872A4/fr not_active Withdrawn
- 2001-05-28 US US10/297,065 patent/US7084136B2/en not_active Expired - Fee Related
- 2001-05-28 AU AU2001260627A patent/AU2001260627A1/en not_active Abandoned
- 2001-05-28 JP JP2002501859A patent/JPWO2001094309A1/ja not_active Withdrawn
- 2001-05-28 WO PCT/JP2001/004430 patent/WO2001094309A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030683A1 (fr) * | 1998-11-19 | 2000-06-02 | Shionogi & C0., Ltd. | Composes prophylactiques et/ou therapeutiques destines a des maladies du systeme nerveux central et possedant des composes antagonistes du recepteur de txa2 et/ou inhibiteurs de la txa2 synthase |
WO2000053573A1 (fr) * | 1999-03-10 | 2000-09-14 | Shionogi & Co., Ltd. | Compositions medicinales renfermant des composes a squelette [2.2.1] et [3.1.1] bicycliques possedant des proprietes antagonistes vis-a-vis des recepteurs de pgd2/txa¿2? |
Non-Patent Citations (2)
Title |
---|
See also references of WO0194309A1 * |
T. TATSUO: "bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives:" JOURNAL OF MEDICINAL CHEMISTRY., vol. 40, no. 22, 1997, pages 3504-3507, XP002428057 USAMERICAN CHEMICAL SOCIETY. WASHINGTON. * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1338594A1 (fr) * | 2000-11-01 | 2003-08-27 | Shionogi & Co., Ltd. | Compositions pharmaceutiques antagonistes du recepteur de pgd2 |
EP1338594A4 (fr) * | 2000-11-01 | 2004-06-16 | Shionogi & Co | Compositions pharmaceutiques antagonistes du recepteur de pgd2 |
US6933317B2 (en) | 2000-11-01 | 2005-08-23 | Shionogi & Co. Ltd. | PGD2 receptor antagonistic pharmaceutical compositions |
US7910613B2 (en) | 2004-09-22 | 2011-03-22 | H. Lundbeck A/S | 2-acylaminothiazole derivatives |
US7674912B2 (en) | 2005-04-25 | 2010-03-09 | H. Lundbeck A/S | Pro-drugs of N-thiazol-2-yl-benzamide derivatives |
Also Published As
Publication number | Publication date |
---|---|
US20040024019A1 (en) | 2004-02-05 |
EP1295872A4 (fr) | 2007-05-16 |
US7084136B2 (en) | 2006-08-01 |
AU2001260627A1 (en) | 2001-12-17 |
JPWO2001094309A1 (ja) | 2004-02-05 |
WO2001094309A1 (fr) | 2001-12-13 |
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